The present invention relates to a minimally invasive system to achieve transdermal crosslinking or polymerization of hydrogels or other polymers for use in drug delivery or tissue engineering.
Fabricating polymers in situ provides many advantages over using preformed polymers for a variety of biomedical applications including drug delivery and tissue engineering. Prepolymerized liquid solution or moldable putties can be placed in an exact location and/or molded into complex shapes. Subsequent polymerization of the prepolymer yields a polymer of exactly the required shape and dimensions in the desired location. However, the formation of polymers in situ presents many challenges. Polymerization reactions which frequently occur by free radical reactions are quite adverse to physiological conditions including a narrow range of acceptable temperatures, requirement for nontoxic monomers and/or solvents, moist and oxygen-rich environments, and the need for rapid processing and clinically suitable rates of polymerization (Elisseeffet al., Proc. Natl. Acad. Sci. USA 96:3104–3107, 1999).
In the field of drug delivery, the implantation of a drug delivery device often involves a surgical procedure to place a formed drug-laden implant into a recipient's body at a desired site. These devices are usually made of a polymer impregnated with a bioactive agent to be delivered and are formed into shapes such as a sphere, cylinder, fibers, slab, or oval. The formed nature of these devices can lead to local irritation and inflammation at the site of implantation. As the polymer of the formed implant is degraded, the agent is gradually released in a controlled manner over an extended period of time. However, with the increased demand to minimize hospitalization stays and decrease patient morbidity, a drug delivery system which would require only a small incision or eliminate the need for a surgical procedure altogether would be very useful.
In the field of tissue engineering, many reconstructive plastic surgical procedures to correct deformities, whether traumatic or congenital, require invasive surgical techniques to place alloplastic prostheses. Griffith-Cima et al. in WO 94/25080 describe the use of injectable polysaccharide-cell compositions for delivering isolated cells by injection, which then form new tissue that is effective as a bulking agent. Sims et al. (Plastic Reconstructive Surgery 98:845, 1996) reported the formation of new cartilage from injected polyethylene oxide-cell suspensions and suggested that this technology would be useful in plastic surgery. A prosthesis which is formed in situ would eliminate the need for invasive surgical techniques.
A method of forming polymers in situ using photopolymerizaton of polymers which form semi-interpenetrating or interpenetrating polymer networks was described in U.S. Patent Application U.S. Ser. No. 08/862,740 by Langer et al. According to this application, one injects into a recipient's body a prepolymer solution which can be crosslinked, and then light is applied externally to the skin to crosslink the injected polymer. With the aid of a photoinitiator, the polymer will crosslink with an amount of light equivalent to 1–3 mW/cm2 applied to the skin of nude mice. The polymer solution may consist of living cells for tissue engineering applications or may contain a bioactive agent for drug delivery applications. Disadvantages of using photopolymerization include exposing the patient and the living cells (in the case of tissue engineering) to potentially harmful ultraviolet rays and the difficulty of providing electromagnetic radiation to most sites within the body.
Other implantable delivery systems are known such as those disclosed by Dunn et al. in U.S. Pat. Nos. 5,739,176; 5,733,950; 5,340,849; 5,278,202; 5,278,201; and 4,938,763. In Dunn's system, a syringeable, in situ forming, solid biodegradable implant is formed in the recipient's body either by 1) the diffusion of a solvent, in which a polymer is dissolved, away from the polymer to produce the implant; or 2) the addition of a curing agent such as benzoyl peroxide or azobisisobutyronitrile to the prepolymer suspension prior to injection. A major drawback to this approach is the use of organic solvents such as N-methyl-2-pyrrolidone, dimethylformamide, and THF which can be toxic or irritating to body tissues. Another drawback is the rapid rate at which the curing agent polymerizes the implant even at room temperature. Therefore, the injection of the prepolymer suspension mixed with the curing agent must take place immediately after addition of the curing agent.
The instant invention avoids the use of organic solvents and ultraviolet radiation which can be harmful, and polymerization and formation of the implant does not take place at an appreciable rate until desired.